Dataset Information

CryoEM structure of Gq-coupled MRGPRX4 with small molecule agonist MS47134

ABSTRACT:

SUBMITTER: Jonathan Firoze Fay

PROVIDER: EMPIAR-10852 | biostudies-other |

REPOSITORIES: biostudies-other

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Publications

Structure, function and pharmacology of human itch GPCRs.

Cao Can C Kang Hye Jin HJ Singh Isha I Chen He H Zhang Chengwei C Ye Wenlei W Hayes Byron W BW Liu Jing J Gumpper Ryan H RH Bender Brian J BJ Slocum Samuel T ST Krumm Brian E BE Lansu Katherine K McCorvy John D JD Kroeze Wesley K WK English Justin G JG DiBerto Jeffrey F JF Olsen Reid H J RHJ Huang Xi-Ping XP Zhang Shicheng S Liu Yongfeng Y Kim Kuglae K Karpiak Joel J Jan Lily Y LY Abraham Soman N SN Jin Jian J Shoichet Brian K BK Fay Jonathan F JF Roth Bryan L BL

Nature 20211117 7887

The MRGPRX family of receptors (MRGPRX1-4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently1. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions2-5. MRGPRX2 couples to both Gi and Gq in mast cells6. Here we describe agonist-stabilized structures of MRGPRX2 coupled to Gi1 and Gq in ter ...[more]

PMID: 34789874

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Project description:G protein coupled receptors (GPCRs) can lead to G protein and non-G protein initiated signals. By virtue of its structural property, the TSH receptor (TSHR) has a unique ability to engage different G proteins making it highly amenable to selective signaling. In this study, we describe the identification and characterization of a novel small molecule agonist to the TSHR which induces primary engagement with Gαq/11. To identify allosteric modulators inducing selective signaling of the TSHR we used a transcriptional-based luciferase assay system with CHO-TSHR cells stably expressing response elements (CRE, NFAT, SRF, or SRE) that were capable of measuring signals emanating from the coupling of Gαs , Gαq/11, Gβγ, and Gα12/13, respectively. Using this system, TSH activated Gαs , Gαq/11, and Gα12/13 but not Gβγ. On screening a library of 50K molecules at 0.1,1.0 and 10 μM, we identified a novel Gq/11 agonist (named MSq1) which activated Gq/11 mediated NFAT-luciferase >4 fold above baseline and had an EC50= 8.3 × 10-9 M with only minor induction of Gαs and cAMP. Furthermore, MSq1 is chemically and structurally distinct from any of the previously reported TSHR agonist molecules. Docking studies using a TSHR transmembrane domain (TMD) model indicated that MSq1 had contact points on helices H1, H2, H3, and H7 in the hydrophobic pocket of the TMD and also with the extracellular loops. On co-treatment with TSH, MSq1 suppressed TSH-induced proliferation of thyrocytes in a dose-dependent manner but lacked the intrinsic ability to influence basal thyrocyte proliferation. This unexpected inhibitory property of MSq1 could be blocked in the presence of a PKC inhibitor resulting in derepressing TSH induced protein kinase A (PKA) signals and resulting in the induction of proliferation. Thus, the inhibitory effect of MSq1 on proliferation resided in its capacity to overtly activate protein kinase C (PKC) which in turn suppressed the proliferative signal induced by activation of the predomiant cAMP-PKA pathway of the TSHR. Treatment of rat thyroid cells (FRTL5) with MSq1 did not show any upregulation of gene expression of the key thyroid specific markers such as thyroglobulin(Tg), thyroid peroxidase (Tpo), sodium iodide symporter (Nis), and the TSH receptor (Tshr) further suggesting lack of involvement of MSq1 and Gαq/11 activation with cellular differentation. In summary, we identified and characterized a novel Gαq/11 agonist molecule acting at the TSHR and which showed a marked anti-proliferative ability. Hence, Gq biased activation of the TSHR is capable of ameliorating the proliferative signals from its orthosteric ligand and may offer a therapeutic option for thyroid growth modulation.

Dataset Information

CryoEM structure of Gq-coupled MRGPRX4 with small molecule agonist MS47134

Publications

Structure, function and pharmacology of human itch GPCRs.

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